ES2369046T3 - USE OF A DPP-IV INHIBITOR TO REDUCE HYPOGLUCEMIC EVENTS. - Google Patents

Abstract

Use of a DPP-IV inhibitor or a salt thereof for the manufacture of a medicament for the reduction of hypoglycemic events or severe hypoglycemic events, in patients being treated with insulin, in which the DPP-IV inhibitor is vildagliptin or a Get out of it.

Description

Use of a DPP-IV inhibitor to reduce hypoglycemic events.

The invention relates to a method for reducing hypoglycemic events, especially severe hypoglycemic events, which result from treatment with antidiabetic compounds especially insulin treatment, in which the patient is treated with a dipeptidyl peptidase IV inhibitor (DPP-IV inhibitor. ) or a pharmaceutically acceptable salt thereof.

Patients treated preferably suffer from hyperglycemia such as diabetes mellitus preferably non-insulin dependent diabetes mellitus or impaired glucose metabolism (IGM) preferably glucose intolerance (IGT).

Diabetes mellitus is a relatively common disorder (approximately 1% prevalence is estimated in the general population) characterized by hyperglycemia. There are three basic types of diabetes mellitus, type I or insulin-dependent diabetes mellites (DMID), type II or non-insulin-dependent diabetes mellites (NIDDM), and type A insulin resistance. Patients with diabetes either type I or type II can Become insensitive to the effects of exogenous insulin ("insulin resistance") through a variety of mechanisms. Type A insulin resistance results from either mutations in the insulin receptor gene or defects in sites of action behind receptors critical for glucose metabolism. Diabetes is usually controlled through the administration of exogenous insulin (especially in type I diabetics), food control and exercise (especially in type II diabetics) or both.

Alteration of glucose metabolism (IGM) is defined by blood glucose levels that are above the normal range but are not high enough to meet the diagnostic criteria for diabetes mellitus type 2. The incidence of IGM varies from from one country to another, but usually occurs 2-3 times more frequently than overt diabetes. Until recently, it was considered that individuals with IGM were prediabetic, but data from several epidemiologic studies argue that subjects with IGM are heterogeneous with respect to their risk of diabetes and your risk of cardiovascular morbidity and mortality. The data suggest that subjects with IGM, particularly with IGT, do not always develop diabetes, but regardless of whether or not they are diabetic, they are nevertheless at high risk of cardiovascular morbidity and mortality. Among subjects with IGM, approximately 58% have glucose intolerance (IGT), another 29% have impaired fasting glucose (IFG), and 13% have both abnormalities (IFG / IGT). IGT is characterized by elevated postprandial hyperglycemia (after food) while IFG has been defined by the ADA (see table below) based on fasting glycemic values.

Normal glucose tolerance (NGT), IGM and type 2 diabetes mellitus categories were defined by the ADA (American Diabetes Association) in 1997.

The fact that IGT is an independent risk factor in non-diabetics as well as in diabetics justifies it being a new indication, separate from diabetes, for the prevention and treatment of cardiovascular morbidity and mortality as well as cancer. In addition, the stage between normoglycemia and type 2 diabetes mellitus, especially the glycemic stage, is becoming of major interest and there is a strong need for a method to inhibit or delay the progression to type 2 diabetes mellitus, and also the variety of diseases and cardiovascular and microvascular states as well as cancer that have been associated with IGM and especially IFG and / or IGT.

Type 2 diabetes is a progressive disease, and although monotherapy can initially control blood glucose in some patients, it is associated with a high rate of secondary failure. This high incidence of therapeutic failure is a major factor contributing to the high rate of complications associated with hyperglycemia long term in patients with type 2 diabetes can overcome the limitations of an individual agent therapy for maintaining glycemic control, the less in some patients, and for a limited period of time, combining multiple oral drugs to achieve reductions in blood glucose that cannot be maintained during long-term therapy with individual agents. The available data support the conclusion that in most patients with type 2 diabetes, oral monotherapy will fail and multiple drug treatment will be required.

However, because type 2 diabetes is a progressive disease, even patients with good initial responses to combination therapy will eventually require an increase in dosage or additional insulin treatment because the blood glucose level is difficult to keep stable for a long period of time.

Although combination therapy has the possibility of improving glycemic control, it does not lack limitations. Many results indicate that the risk of hypoglycemia can be increased with combination therapy, and the requirement of multiple medications can also reduce patient compliance. In addition, taking multiple antihyperglycemic drugs increases the possibility of pharmacokinetic interactions with other medications that the patient may be taking.

The rational use of oral combination therapy can temporarily delay the need for multiple insulin injections, facilitate temporarily the maintenance of low glucose level or a level of glycosylated hemoglobin (HbA1c) low and temporarily help prevent vascular complications.

The applicant has surprisingly discovered that DPP-IV inhibitors especially LAF237 can be used in combination with antidiabetic compounds, especially in combination with insulin treatment, to reduce severe hypoglycemic events that result from treatment with antidiabetic compounds especially insulin treatment. In addition, long-term treatment with such a combination presents significantly less inconvenience than other combinations, for example insulin in combination with a glitazone.

Insulin is a known compound approved by Food & U.S. Drugs Administration UU. for the therapeutic treatment of diabetes.

In the present context it is intended that the term "insulin" also comprises any form of insulin or any derivative thereof as described in US Patent 6,620,780.

Human insulin has three primary amino groups: the N-terminal group of chain A and chain B and the ε-amino group of LysB 29. Several insulin derivatives that are substituted in one or more of these groups are known from prior art Thus, US Patent No. 3,528,960 (Eli Lilly) refers to N-carboxyroxy insulins in which one, two or three primary amino groups of the insulin molecule have a carboxyroyl group. No specifically N εB29-substituted insulin is described.

According to British Patent No. 1,492,997 (Nat. Res. Dev. Corp.), it has been found that insulin with a carbamyl substitution in N εB29 has an improved hypoglycemic effect profile.

Patent application open for public consultation 1-254699 (Kodama Co., Ltd.) discloses insulin in which a fatty acid is attached to the amino group of Phe B1 or the ε-amino group of Lys B29 or both. The stated purpose of derivatization is to obtain a stable, pharmacologically acceptable insulin preparation.

In the open patent application for public consultation JP No. 57-067548 (Shionogi) describe insulins that in the B30 position have an amino acid having at least five carbon atoms that may not necessarily be encoded by a triplet of nucleotides Insulin analogs are claimed that are useful in the treatment of diabetes mellitus, particularly in patients who are insulin-resistant due to the generation of bovine or porcine antibodies against insulin.

U.S. Patent No. 5,359,030 (Ekwuribe, Delivery Protein, Inc.) describes conjugated stabilized polypeptide compositions for oral or parenteral administration comprising a polypeptide covalently coupled with a polymer that includes a linear polyalkylene moiety and a lipophilic moiety. , said moieties being arranged relative to each other so that the polypeptide exhibits an increase in resistance in vivo to enzymatic degradation.

EP 511600 A2 refers to protein derivatives of the formula [protein] [Z] n in which the [protein] represents a protein that has n amino residues that can each be derived from an amino group by removing one of their hydrogen atoms, instead of the amino groups, [Z] is a residue represented by the formula -CO-W-COOH in which W is a divalent long chain hydrocarbon group which may also contain certain heteroatoms and n represents an average number of amide bonds between [Z] and [protein]. It is mentioned that the protein derivatives of the invention have an extremely prolonged serum half-life compared to the proteins from which they are derived and which do not show antigenicity. It is also mentioned that insulin is one of the proteins from which derivatives according to the invention can be prepared, but no specific insulin derivatives are disclosed in EP 511600 nor is there any indication of a

[Z] preferred or a preferred position (s) in which [Z] must be introduced in order to obtain useful insulin derivatives.

In the present specification, whenever the term insulin is used in a generic or plural sense, it is intended to encompass both naturally occurring insulins and insulin analogs and derivatives thereof. By "insulin derivative" as used herein is meant a polypeptide having a molecular structure similar to that of human insulin including the disulfide bridges between Cys A7 and Cys B7 and between Cys A20 and Cys B19 and an internal disulfide bridge between Cys A6 and Cys A11, and they have insulin activity.

Preferably, insulin is in the form of a pharmaceutical composition which is a solution containing from about 30 nmol / ml to about 3000 nmol / ml, or 120 nmol / ml to 1200 nmol / ml about 600 nmol / ml of insulin.

They are examples of insulins;

NovoLog® (insulin injection aspart [rDNA origin]) is a human insulin analog that is a rapid-acting parenteral hypoglycemic agent. The dosage of NovoLog should be individualized and determined based on the advice of the doctor, according to the needs of the patient. The need for total daily individual insulin is usually between 0.5 and 1.0 units / kg / day. When used in a treatment regimen with subcutaneous food-related injections, 50-70% of total insulin needs can be provided by NovoLog and the rest can be provided by an intermediate-acting or long-acting insulin.

APIDRAT ™ (insulin glulisine [rDNA origin]) is a human insulin analog that is a rapid-acting parenteral hypoglycemic agent. Insulin glulisine is produced by recombinant DNA technologies using a non-pathogenic laboratory Escherichia coli (K12) strain. Insulin glulisin differs from human insulin in that the amino acid asparagine in position B3 is replaced by lysine and lysine in position B29 is replaced by glutamic acid. Chemically, it is human insulin-3B-lysine-29B-glutamic acid, which has the empirical formula C258H384N64O78S6 and a molecular weight of 5823. APIDRA 100 units per ml (U-100) is available in the following package size: 10 vials ml NDC 0088-2500-33. The dosage of APIDRA should be individualized and determined based on the advice of the doctor according to the needs of the patient. APIDRA should normally be used in regimens that include long-acting insulin or basal insulin analogues

Humalog (insulin lispro, rDNA origin) is a human insulin analog that is a rapid-acting parenteral hypoglycemic agent. Chemically, it is the human insulin analogue Lys (B28), Pro (B29), created when the amino acids at positions 28 and 29 in the insulin B chain are inverted.

LANTUS® (insulin glargine injection [rDNA origin]) is a sterile insulin glargine solution for use as an injection. Insulin glargine is a recombinant human insulin analog that is a long-acting parenteral hypoglycemic agent (up to 24-hour duration of action). (See CLINICAL PHARMACOLOGY). LANTUS is produced by recombinant DNA technologies using a non-pathogenic laboratory Escherichia coli (K12) strain as a production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C terminus of chain B. In a clinical study of patients not previously treated with insulin diabetes type 2 already treated with oral antidiabetic drugs, LANTUS was started at an average dose of 10 IU once a day, and subsequently adjusted according to the patient's need up to a total daily dose ranging from 2 to 100 IU.

Exubera® is an inhaled short-acting insulin preparation indicated for the treatment of type 1 and type 2 diabetes and developed by Pfizer (human insulin [rDNA origin), inhalation powder). Exubera® is a fast-acting, dry-acting human insulin that is inhaled through the mouth into the lungs before eating, using the Exubera® portable inhaler.

The term "DPP-IV" is intended to indicate a molecule that exhibits inhibition of the enzymatic activity of DPP-IV and functionally related enzymes, such as from 1-100% inhibition, and specially preserves the action of substrate molecules, including but not limited to glucagon-like peptide-1, gastric inhibitor polypeptide, histidine-methionine peptide, substance P, neuropeptide Y, and other molecules that normally contain alanine or proline residues in the second amino terminal position. Treatment with DPP-IV inhibitors prolongs the duration of the action of the peptide substrates and increases the levels of their intact non-degraded forms which leads to a spectrum of biological activities relevant to the invention disclosed.

DPP-IV can be used in the control of glucose metabolism because its substrates include the insulinotropic hormones like peptide-1 glucagon (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; the elimination of its two amino acids from the N-terminal end inactivates them. In vivo DPP-IV Synthetic administration prevents degradation of N-terminal GLP-1 and GIP end, resulting concentrations higher plasma of these hormones, increased insulin secretion and, therefore , an improved glucose tolerance. To that end, chemical compounds are tested to determine their ability to inhibit the enzymatic activity of purified CD26 / DPP-IV. In summary, the activity of CD26 / DPPIV is measured in vitro for its ability to cleave the synthetic substrate Gly-Pronitroanilide (Gly-Pro-pNA). The cleavage of Gly-Pro-pNA by DPP-IV releases the product p-nitroanilide (pNA), whose rate of appearance is directly proportional to the activity of the enzyme. Inhibition of enzyme activity by specific enzyme inhibitors slows the generation of pNA. The most intense interaction between an inhibitor and the

Enzyme results in a slower generation rate of pNA. Therefore, the degree of inhibition of the pNA accumulation rate is a direct measure of the strength of enzyme inhibition. The accumulation of pNA is measured with a spectrophotometer. The inhibition constant, Ki, for each compound is determined by incubating fixed amounts of the enzyme with several different concentrations of inhibitor and substrate.

In the present context "a DPP-IV inhibitor" refers to: 1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-, (S) (also called (S) -1- [ (3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine, LAF237 or vildagliptin) of formula

and you leave it.

LAF237 is specifically disclosed in example 3 of WO 98/19998 and in example 1 of WO 00/34241. LAF237 can be formulated as described on page 20 of WO 98/19998 or in WO 00134241, or in international patent application No. EP2005 / 000400 (application number).

The DPP-IV inhibitor to be used only according to the present invention can be used in association with a carrier, in which the DPP-IV inhibitor is LAF. A carrier in the present context is a tool (natural, synthetic, peptide, non-peptide) for example a protein that transports specific substances through the cell membrane in which it is embedded and into the cells. Different carriers (natural, synthetic, peptide, non-peptide) are required to transport different substances, since each is designed to recognize only one substance, or a group of similar substances.

Any detection means known to those skilled in the art can be used to detect the association of LAF with a carrier, for example, by marking the carrier. Most preferred is oral active LAF and pharmaceutical salts thereof.

The LAF active ingredients or pharmaceutically acceptable salts thereof according to the present invention can also be used in the form of a solvate, such as a hydrate or including other solvents, used for crystallization.

Surprisingly it has now been found that LAF237 can be used in combination with insulin to reduce severe hypoglycemic events resulting from insulin treatment. Therefore, in a first embodiment, this invention provides a method for the reduction of severe hypoglycemic events comprising administering a therapeutically effective amount of LAF or a salt thereof, to a patient treated with insulin.

Or a method of reducing hypoglycemic events or severe hypoglycemic events resulting from insulin treatment, which comprises administering a therapeutically effective amount of LAF or a salt thereof, to a patient treated with insulin.

Or the use of LAF or a salt thereof, in combination with insulin for the manufacture of a medicament for the reduction of hypoglycemic events or severe hypoglycemic events.

Or the use of LAF or a salt thereof, for the manufacture of a medicament for the reduction of hypoglycemic events or severe hypoglycemic events, in patients being treated with insulin.

Use as described herein, in which hypoglycemic events or severe hypoglycemic events result from insulin treatment, ie as a result of insulin treatment.

The terms "hypoglycemic event" or "hypoglycemic episode" are well known to those skilled in the art. Hypoglycemia was defined as symptoms that suggest low blood glucose confirmed by OMBG <3.1 mmol / l of plasma glucose equivalent. Severe hypoglycemia was defined as any episode that requires the assistance of a third party (with a plasma glucose value of <3.1 mmol / l unless the severity of the event discards the glucose determination). Therefore according to the present invention, the term

"Severe hypoglycemia" is preferably defined as an episode with low plasma glucose value <3.8 mmol / l, preferably <3.1 mmol / l.

The DPP-IV inhibitor is (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine (LAF237 or vildagliptin) of formula (I)

or a pharmaceutically acceptable salt thereof.

In the present context, the terms "(S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine" or "LAF237" or "vildagliptin" are also intended to comprise any crystalline salt or form Of the same.

The antidiabetic compound is insulin.

Preferably, the patient treated according to the invention suffers from hyperglycemia, most preferably the patient suffers from a disease selected from diabetes mellitus, type 1 or insulin-dependent diabetes mellitus (DMID), type II or non-insulin dependent diabetes mellitus (NIDDM), resistance to Type A insulin, impaired glucose metabolism (IGM), impaired fasting glucose (IFG) or glucose intolerance (IGT). In a preferred embodiment, the patient suffers from type II diabetes or IGT.

In the most preferred embodiment, LAF or a salt thereof, is added to the treatment of conventional diabetes in patients whose disease, that is, diabetes, was not adequately controlled with insulin alone.

The skilled artisan knows the criteria for assessing the proper control of the disease and described in the literature for example every year by the American Diabetes Association Diabetes Care publication (Standards of Medical Care in Diabetes 2006 -29: S4 -42S).

Current methods or uses are particularly useful for prevention or to delay the progression of conditions associated with type II or IGT diabetes, particularly cardiovascular and microvascular states.

The invention further relates to the use of LAF or a salt thereof, for the manufacture of a medicament to reduce the hypoglycemic events or sever hypoglycemic events, in insulin treated patient, particularly in a patient (eg a diabetic patient type II) not adequately controlled with insulin alone, i.e. diabetes or glucose level not adequately controlled with at least one antidiabetic compound or insulin alone.

Preferably, the invention relates to the use of LAF or a salt thereof, in combination with insulin, for the manufacture of a medicament for reducing hypoglycemic events or severe hypoglycemic events in a patient (for example type II diabetic patient) not adequately controlled with insulin alone, that is, diabetes or glucose level not adequately controlled with insulin alone.

Method or use as described herein, in which 25 to 150 mg, preferably 50 mg or 100 mg of vildagliptin, or a salt thereof, preferably daily (daily dose) should be administered. In addition, as used herein, "a daily dose" means the dose administered within a 24-hour period. The term "prevention" means prophylactic administration of the combination to healthy patients to prevent the occurrence of the states mentioned herein. In addition, the term "prevention" means prophylactic administration of such a combination to patients who are in a pre-stage of the states, which must be treated.

The term "delay progression" used herein means the administration of the combination, such as a pharmaceutical composition or combination preparation, to patients who are in a pre-stage of the state to be treated in which the patients are diagnosed. a preform of the corresponding state.

The term "treatment" means the management and care of a patient with the purpose of combating the disease, condition, or disorder.

As used herein, the term "patient" refers to an animal suffering from hyperglycemia or diabetes or IGM. The preferred animal is a mammal, such as dogs, cats, horses, cows and humans. It is preferred that the patient be a human being.

In this field, the age of the preferred patient population is from 45 years onwards, being most preferred from 60 years onwards.

The skilled artisan is fully trained to select a relevant test model and protocols to test the beneficial effects of the invention.

Monitoring of glycemic status, performed by patients and healthcare professionals, is well known in the art as reported in Diabetes Care "Tests of Glycemia in Diabetes -American Diabetes Association" 2003 26: S106-108 and described below. . This publication is incorporated herein by reference in its entirety.

The American Diabetes Association technical review should be consulted for additional information (eg Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Paterson CM: Tests of glycemia in diabetes (Technical Review). Diabetes Care 18: 896 -909, 1995).

In just a few years, self-monitoring of blood glucose (SMBG) by patients has revolutionized diabetes management. Using SMBG, patients with diabetes can work to achieve and maintain specific glycemic goals,

The SMBG issue has been discussed extensively in two consensus conferences of the American Diabetes Association, which provide a comprehensive review of the issue (American Diabetes Association: Self-monitoring of blood glucose (Consensus Statement). Diabetes Care 17: 81- 86, 1994-and-American Diabetes Association: Selfmonitoring of blood glucose (Consensus Statement). Diabetes Care 90: 93.-99, 1987). SMBG has replaced urine glucose tests for most patients. Urine glucose tests for patients at home consist of semi-quantitative measurements based on individual evacuations or, less frequently, on more quantitative “blocks” collected over 4-24 hours. The rationale is that urine glucose values reflect average blood glucose during the urine collection period.

Urine and blood glucose tests and urine ketone tests provide useful information for managing day-to-day diabetes.

However, these tests cannot provide the patient and healthcare team with a quantitative and reliable measure of blood glucose for a prolonged period of time. Measurements of glycosylated proteins, mainly hemoglobin and serum proteins, add a new dimension to the glycemic evaluation. With a single measurement, each of these tests can quantify the average blood glucose for weeks and months, thus complementing the day-to-day tests.

Glycosylated hemoglobin (GHb) tests:

GHb, also called glycohemoglobin, glycosylated hemoglobin, HbA1c, or HbA1, is a term used to describe a series of minor and stable components of hemoglobin formed non-enzymatically and slowly from hemoglobin and glucose. The rate of GHb formation is directly proportional to the concentration of glucose in the environment. Since erythrocytes are freely permeable to glucose, the level of GHb in a blood sample provides a glycemic history of the previous 120 days, the average lifespan of the erythrocyte. GHb more accurately reflects the previous 2-3 months of glycemic control.

It has many different types of test methods GHb for routine clinical laboratory, for example HbA1c can be measured by liquid chromatography (HPLC) using the ion exchange method in Diamat analyzer Bio-Rad. A support affinity method is used if hemoglobin variants or hemoglobin degradation peaks are observed.

The methods differ considerably with respect to the measured glycosylated components, the interferences, and the non-diabetic range. Glycosylated hemoglobin is frequently reported as hemoglobin A1c. HbA1c has become the preferred pattern for the evaluation of glycemic control. In reference to this test, the term "A1 C test" will be used.

A1C tests should be performed routinely in all patients with diabetes, first to document the degree of glycemic control in the initial evaluation, then as part of ongoing care. Since the A1C test reflects a mean glycemia during the previous 2-3 months, a measurement is required approximately every 3 months to determine whether the patient's metabolic control has been achieved and has been maintained within the target range or not.

The A1 C test has been shown to predict the risk for the development of many of the chronic complications in diabetes, similar to using cholesterol determinations to predict the risk of developing cardiovascular disease.

Glycosylated serum protein (GSP)

Because the turnover of human serum albumin is much shorter (half-life of 14-20 days) than that of hemoglobin (120-day erythrocyte shelf life), the degree of glycosylation of serum proteins (mainly albumin) provides a glycemic index for a shorter period of time than that of hemoglobin glycosylation. The measurements of total GSP and glycosylated serum albumin (GSA) correlate well with each other and with measurements of glycosylated hemoglobin (A1 C test). In situations where the A1C test cannot be measured or may not be useful (for example, hemolytic anemias), the GSP test may be valuable in evaluations of the treatment regimen. Several methods have been described that quantify either the total GSP or the total GSA. One of the most widely used is called the fructosamine assay. Values for GSP vary with changes in the synthesis or clearance of serum proteins that may occur with acute systemic disease or with liver disease. In addition, there is an ongoing debate as to whether or not fructosamine assays should be corrected for serum protein or serum albumin concentrations.

A single GSP measurement provides a glycemic status index during the previous 1-2 weeks, while a single A1C test provides a glycemic status index for a considerably longer period of time, 2-3 months.

The measurement of GSP, regardless of the specific test method, should not be considered equivalent to the A1 C test, since it only indicates glycemic control for a short period of time. Therefore, GSP trials would have to be performed monthly to obtain the same information as measured by the A1 C test three to four times a year. Unlike the A1C test, the GSP has not yet been shown to be related to the risk of development or progression of chronic diabetes complications.

Doctors are well aware of glucose level progression checks (for example, GSP test, A1C, insulin) and are reported in the art for example by the American Diabetes Association.

The invention also relates to a treatment regimen, for the treatment of diabetes, for example type 2 diabetes, in which,

one.

a patient treated with insulin and not adequately controlled with insulin alone is selected,

2.

should be administered between 26 and 100 mg, preferably 50 mg or 100 mg of (S) -1 - [(3-hydroxy-1-amyl) amino] acetyl-2-cyano-pyrrolidine, or a salt thereof, in combination with insulin , daily, to said patient.

The invention also relates to a treatment regimen, for the treatment of diabetes, for example, type 2 diabetes in which,

one.

a patient treated with at least one antidiabetic compound (for example one, two or three) and not adequately controlled with insulin alone is selected,

2.

should be administered between 25 and 150 mg, preferably 50 mg or 100 mg of (S) -1 - [(3-hydroxy-1-amyl) amino] acetyl-2-cyano-pyrrolidine, or a salt thereof, in combination with insulin , daily, to said patient.

In the above described treatment regimen, the term "daily" it applies to insulin and (S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine (vildagliptin) or only to ( S) -1 - [(3-hydroxy-1-adamantyl) amino] acetyl-2-cyano-pyrrolidine (vildagliptin) for example when the patient contains within the body an insulin pump administering daily insulin dosage or any related device.

The invention also relates to a treatment regimen, for the treatment of diabetes, for example type 2 diabetes in which,

1) a patient treated with insulin is selected and shows hypoglycemic episodes, preferably severe hypoglycemic events,

2) 25 to 150 mg, preferably 60 mg or 100 mg of (S) -1 - [(3-hydroxy-1-amantil) amino] acetyl-2-cyano-pyrrolidine should be administered in combination with insulin, daily, to said patient .

The invention also relates to a treatment regimen, for the treatment of diabetes, for example type 2 diabetes in which,

1) a patient treated with insulin is selected and shows hypoglycemic episodes, preferably severe hypoglycemic events,

2) LAF or a salt thereof in combination with insulin should be administered daily to said patient.

The invention also relates to a treatment regimen, for the treatment of diabetes, for example type 2 diabetes in which,

1) a patient treated with insulin is selected and shows hypoglycemic episodes, preferably severe hypoglycemic events,

2) 25 to 150 mg should be administered, preferably 50 mg or 100 mg of (S) -1 - [(3-hydroxy-1-amyl) amino] acetyl-2-cyano-pyrrolidine or a salt thereof, in combination with insulin, daily, to said patient.

3) the daily dose or dose of insulin is progressively reduced until the desired glucose level is achieved, that is, the blood glucose level, for example, by means of an analysis of the level of HbA1c in the blood.

Insulin, depending on its form of administration, can be administered for example regularly throughout the day, twice a day, once a day, every 2 or 3 days.

The invention also relates to a treatment regimen, for the treatment of diabetes, for example type 2 diabetes in which,

1) a patient treated with insulin is selected and shows hypoglycemic episodes, preferably severe hypoglycemic events,

2) 25 to 150 mg should be administered, preferably 50 mg or 100 mg of (S) -1 - [(3-hydroxy-1-amyl) amino] acetyl-2-cyano-pyrrolidine or a salt thereof, in combination with a dose of insulin reduced, daily, to said patient.

A treatment, method or use regimen as described herein in which between 25 mg and 200 mg of LAF or a salt thereof is administered daily to the treated patient. The preferred daily administration of sitagliptin is between 25 and 100 mg.

A treatment, method or use regimen as described herein, in which the treated patient suffers from insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM)

or insulin resistance type A.

A treatment regimen, method or use as described herein in which LAF can be administered in combination with insulin LAF.

Preferably, the patient treated in the methods or uses described above suffers from hyperglycemia and hypoglycemic events, for example, severe hypoglycemic events after insulin administration. Most preferably. the patient suffering from hyperglycemia, suffers from a disease selected from diabetes mellitus, type 1 or insulin-dependent diabetes mellitus (DMID), type II or non-insulin-dependent diabetes mellitus (DMNID), insulin resistance type A, IGM, IFG or IGT. In a preferred embodiment, the patient suffers from type II diabetes or IGT. In another preferred embodiment, the treated patient is a patient whose disease, for example, hyperglycemia or glucose level, was not adequately controlled with insulin alone. In another preferred embodiment, the treated patient is a patient whose disease, for example, hyperglycemia or glucose level, was not adequately controlled with at least one antidiabetic compound.

The structure of active agents identified by code numbers, generic or commercial names can be taken from the current edition of the compendium of "The Merck Index" standards or databases, for example international patents (for example IMS World Publications). The corresponding content is incorporated herein by reference. Any person skilled in the art is fully trained to identify the active ingredients and, based on these references, also trained to manufacture and test the

Pharmaceutical indications and properties in conventional test models, both in vitro and in vivo.

The pharmaceutical preparations described herein are for enteral administration, such as oral, and also rectal or parenteral, to homeotherms, the preparations comprising the pharmacological active ingredient either alone or together with usual pharmaceutical auxiliary substances. For example, pharmaceutical preparations consist of from about 0.1% to 90%, preferably from about 1% to about 80%, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration, and also by ocular administration, are, for example, in unit dosage forms, such as coated tablets, tablets, areas or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubilization or lyophilization procedures. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if a mixture has been obtained desired granulating, and, if required or necessary, processing the mixture or granulate it to yield tablets or cores of coated tablets after adding the appropriate auxiliary substances.

The dosage of the active substance may depend on a variety of factors, such as the mode of administration, homeothermal species, age and / or the condition of the individual.

Preferred dosages, for those active ingredients of the pharmaceutical combination according to the present invention that are commercially available, are especially commercially available therapeutically effective dosages.

The dosage of the active substance may depend on a variety of factors, such as the mode of administration, the homeothermic species, the age and / or the condition of the individual.

The corresponding active ingredient or a pharmaceutically acceptable salt thereof can also be used in the form of a hydrate or include other solvents used for crystallization.

The exact dosage will of course vary depending on the compound employed, the mode of administration and the desired treatment. The compound can be administered by any conventional route, non-oral route or preferably oral route.

In general, LAF237 is administered in a daily dosage of from about 0.01 to 50 mg / kg, the most preferred doses range from 0.1 to 50 mg / kg.

Insulin treatment is well described in the art.

For larger mammals, a total daily dosage indicated is in the range from about 0.01 to 100 mg / kg of the compound, conveniently administered in divided doses 2 to 4 times a day in unit dosage forms containing for example from about 0.1 to about 50 mg of the compound in a sustained release form.

Preferably, the indicated total daily dosage of LAF237 is in the range of between 1 and 500 mg, preferably between 10 and 200 mg of the active substance. Preferably, the daily oral dosage of LAF237 is between 1 and 100 mg, preferably between 10 and 100 mg, for example 10 mg, most preferably between 25 and 100 mg for example 25 mg or 30 or 40 or 50, 61, 70, 90, 100, 150 mg. The most preferred daily oral dosage of LAF237 is between 50 and 100 mg.

Unit doses suitable for oral administration contain, for example, from about 25 to about 200, or from about 25 to about 100 mg of LAF237, such as preferably 25, 50 or 100 mg. The appropriate doses for parenteral administration contain for example from about 1 to about 100 mg of the compound, for example from 10 to 50 mg.

LAF can also be administered every day or only every other day, or twice a week.

The compounds can be administered similarly to known standards for use in these utilities. The proper daily dosage for a particular compound will depend on several factors such as its relative potency of activity. A person skilled in the relevant art is fully trained to determine the therapeutically effective dosage.

The compound of the invention can be administered as a free base or as a quaternary ammonium salt or pharmaceutically acceptable acid addition salt. Such salts can be prepared in a conventional manner and show the same order of activity as the free forms. If these compounds have, for example, at least one basic center, they can form an acid addition salt. The corresponding acid addition salt can also be formed so that it has, if desired, an additionally present basic center. Compounds having an acidic group (for example COOH) can also form salts with bases. For example, the compounds to be combined may be present as a sodium salt as a maleate or as a dihydrochloride. The active ingredient or a pharmaceutically acceptable salt thereof can also be used in the form of a hydrate or include other solvents used for crystallization.

A combined preparation comprising LAF in free form or of a pharmaceutically acceptable salt and insulin and optionally at least one, that is, one or more, for example two, pharmaceutically acceptable carriers for simultaneous, separate or sequential use is especially a "kit of parts" in the sense that the components of LAF in free form or of a pharmaceutically acceptable salt and insulin can be dosed independently or by using different formulations with different amounts of the components, ie at different points of time or simultaneously. The parts of the parts kit can then be administered, for example, simultaneously or chronologically staggered, that is to say at different time points and with equal or different time intervals for any part of the parts kit. Preferably, the time intervals are chosen so that the effect on the disease or condition treated in the combined use of the parts is longer than the effect that would be obtained by using only any one of the components.

A therapeutically effective amount of each of the components of the combination of the present invention can be administered simultaneously or sequentially and in any order, and the components can be administered separately or as a fixed combination.

The pharmaceutical compositions according to the invention can be prepared in a manner known per se and are suitable for enteral administration, such as oral or rectal, and parenteral to mammals (warm-blooded animals), including man, which comprises a therapeutically effective amount. of the pharmacologically active principle, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral administration.

To further illustrate the invention, but not by way of limitation, the following study is provided.

The invention has been described above with reference to the preferred embodiments but, as those skilled in the art will appreciate, many additions, omissions and modifications are possible within the scope of the claims below.

Example 1:

CLINICAL STUDY

Insulin is used as a representative compound of antidiabetic compounds that induce hypoglycemic episodes. Equivalent studies with other antidiabetic compounds can be performed (for example one, two

or three) to show the claimed unexpected advantage of DPP-4 inhibitors.

Protocol Overview

Title of the study:

Parallel, randomized, double-blind, multicenter group study to compare the effect of 24-week treatment with 50 mg bid of LAF237 with placebo as a complementary therapy in patients with type 2 diabetes treated with insulin.

Purpose of the study:

The present study is designed to demonstrate the efficacy and safety of complementary therapy with 50 mg bid of LAF237 in patients with type 2 diabetes treated with insulin. This study supports the global normative approval of LAF237 as a combination therapy with insulin in the treatment of type 2 diabetes.

Goals:

Primary objective: To demonstrate the efficacy of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin by testing the hypothesis that the reduction of HbA1c with 50 mg bid of LAF237 is greater than that obtained with placebo after 24 weeks of treatment .

Secondary: Critical variables 1-Demonstrate the efficacy of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin by testing the hypothesis that the reduction of fasting plasma glucose (FPG) with 50 mg bid of LAF237 is superior to that of placebo after 24 weeks of treatment.

2-Demonstrate the safety of LAF237 in patients with type 2 diabetes treated with insulin showing that complementary therapy with 50 mg bid of LAF237 has a similar adverse event profile compared to placebo after 24 weeks of treatment.

3-Demonstrate the efficacy of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin showing that the average reduction in daily insulin dosage and the average reduction in the number of daily insulin injections in combination with 50 mg bid of LAF237 are greater than those obtained with placebo after 24 weeks of treatment.

4-Demonstrate the efficacy of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin showing that the rates of patients responding to treatment with 50 mg bid of LAF237 are higher than those obtained with placebo after 24 weeks of treatment.

5-Demonstrate the efficacy of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin through initial HbA1 c subgroups to assess whether the therapeutic efficacy of LAF237 (decreasing HbA1c with 50 mg bid versus placebo) is or not higher in patients with high initial HbA1c (> 9%) than in patients with low initial HbA1c (<9%) after 24 weeks of treatment.

Scan variables

1-To explore the mechanism of action of LAF237 in complementary therapy in patients with type 2 diabetes treated with insulin by testing the hypothesis that 50 mg bid of LAF237 improves the function of beta cells (classified by fasting proinsulin concentration , the ratio of fasting proinsulin / insulin and HOMA B) and reducing insulin resistance (classified by fasting insulin concentration and IR HOMA) with respect to placebo after 24 weeks of treatment.

2-To explore the secondary clinical benefits of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin by testing the hypothesis that 50 mg bid of LAF237 has a beneficial effect on fasting and neutral plasma lipid profiles for body weight with respect to placebo after 24 weeks of treatment.

3. To explore the secondary benefits of complementary therapy with LAF237 in patients with type 2 diabetes treated with insulin showing that 50 mg bid of LAF237 has a favorable effect on quality of life, patient satisfaction and productivity at work with respect to to placebo after 24 weeks of treatment.

Population:

Patients with type 2 diabetes who are inadequately controlled with insulin can benefit from intensifying their insulin regimen or by adding an oral antidiabetic agent. In this study, 30 units of insulin per day for a minimum of 4 weeks before visit 1, will be eligible to participate in this study.

The population will consist of female and male patients (not fertile or unable to have children when using a medically approved contraceptive method) from 18 to 80 years of age, with HbA1c of 7.5-11%.

This is a multi-center outpatient study that will be conducted in approximately 80 centers in the United States and Europe. Approximately 384 patients will be selected in order to randomize 192 patients.

Inclusion / exclusion criteria:

Inclusion criteria: male or female patients (not fertile or unable to have children when using a medically approved contraceptive method) with type 2 diabetes, previously treated with insulin for at least 3 months, 18-80 years old, index of body mass of 22-45 kg / m2; HbA1c 7.5-11% inclusive, FPG 270 mg / dl. (15 mmol / l) and agree to maintain the previous diet and exercise. Exclusion criteria: pregnant women

or breastfeeding; history of type 1 diabetes, diabetes that is a result of pancreatic injury or secondary forms of diabetes, acute metabolic diabetic complications within the last 6 months; evidence of significant diabetic complications; acute infections that may affect glycemic control within the last 4 weeks; Torsades de Pointes, ventricular tachycardia, ventricular fibrillation; percutaneous coronary intervention in the last 3 months; myocardial infarction, aortocoronary bypass surgery or unstable angina pectoris within the last 6 months; congestive heart failure NYHA class III or IV; second degree AV block (Mobitz 1 and 2), third degree AV block, prolonged QTc interval; malignant tumor including leukemia and lymphoma within the last 5 years; liver disease; acromegaly or growth hormone treatment; treatment with any oral antidiabetic medication within the last 3 months; treatment with an insulin pump; chronic parenteral or oral corticosteroid treatment within the last 8 weeks; treatment with class Ia, Ib, Ic, or III antiarrhythmic agents; significant laboratory abnormalities.

Reference and research therapy:

In addition to insulin treatment, patients are assigned a double-blind 50 mg bid of LAF237

or placebo at a ratio of 1: 1.

Study design:

This is a study of parallel, randomized, double-blind, multicenter groups. Patients with type 2 diabetes (HbA1c 7.5-11%) who have been treated for at least 3 months with insulin are eligible for participation in the trial. Eligible patients are randomized equally to 50 mg bid of LAF237 or placebo in addition to continuing their insulin therapy. The insulin dose may be adjusted in a descending manner as clinically indicated but the ascending adjustments should not exceed 25% of the initial insulin dose.

Each patient attends a review visit (week 4) in which the inclusion / exclusion criteria are evaluated. Eligible patients are then randomized on visit 2 (initial level, day 1) and complete 5 additional visits over a 24-week period of treatment with LAF237 or placebo added to insulin.

Efficacy Assessments:

Main efficacy evaluations: HbA1c; Secondary efficacy evaluations: fasting plasma glucose, fasting lipids (triglycerides, total cholesterol, calculated LDL, HDL, non-calculated HDL, calculated VLDL), body weight, beta cell function (fasting proinsulin, proinsulin / insulin ratio in fasting, HOMA B), insulin resistance (fasting insulin, HOMA IR), average daily insulin dose, average number of daily insulin injections and rates of patients responding to treatment. Patients with type 2 diabetes who have been treated with insulin for at least 3 months, and at least.

Other evaluations:

Safety assessments include monitoring of adverse events, vital signs, physical examinations, laboratory evaluations (hematology, biochemistry and urinalysis), and electrocardiograms. Other evaluations include questionnaires on quality of life.

Analysis of data:

The hypothesis to test the superiority of 50 mg bid of LAF237 over placebo, both LAF237 and placebo combined with insulin, for the purpose of reducing HbA1c will be H0: δ50 mg bid of LAF = δ Placebo versus Ha: δ50 mg bid of LAF different from δPlacebo in which δ is the average change with respect to the initial level in the treatment group indicated by the subscript. A covariance analysis model (ANCOVA) is included including treatment terms, initial HbA1c and region. The average change for least squares (“adjusted mean”) is obtained from the initial level for each treatment group, the difference in the mean changes for least squares between the two treatment groups (50 mg bid of LAF237 -placebo), and The 95% bilateral confidence interval for the difference together with the p-value for the treatment comparison obtained from the primary and presented analysis model. Secondary efficacy variables are evaluated using a similar model.

Patients were instructed to make measurements of the glycemia monitored by themselves. (SMBG) anytime you suspect hypoglycemia and before breakfast at least 3 times a week. Hypoglycemia was defined as symptoms suggesting low blood glucose confirmed by SMBG <3.1 mmol / l of plasma glucose equivalent. Severe hypoglycemia was defined as any episode that required the assistance of third parties (with plasma glucose value below <3.1 mmol / l unless the severity of the event ruled out the glucose determination).

Therefore, according to the present invention, the term "severe hypoglycemia" is preferably defined as an episode of plasma glucose value under <3.8 mmol / l, preferably <3.1 mmol / l.

All laboratory evaluations were performed by central laboratories. HbA1c was quantified with HPLC methodology in reference to the DCCT standard in a level 1 certified laboratory of the National Glycohemoglobin Standardization Program (NGSP) (Bioanalytical Research Corporation [BARC] -EU, Ghent, Belgium or Covance-US, Indianapolis, IN ) or in a laboratory in the NGSP network (Diabetes Diagnostic Laboratory, Columbia, MO). The rest of the laboratory evaluations were carried out by BARC-US (Lake Success, NY) or BARC-EU. Rehearsals are

5 performed according to validated and standardized procedures according to Good Laboratory Practices.

Results:

The data confirm that LAF237 is associated with fewer severe hypoglycemic episodes when added to insulin. Patients treated with insulin only show a significantly higher number of hypoglycemic episodes, especially severe hypoglycemic episodes (1). Patients treated with insulin and

10 LAF237 did not show any severe hypoglycemic episode (1).

(1) Grade 2 hypoglycemic episodes: Glycemia <3.1 and symptoms suggesting hypoglycemia.

Vildagliptin (LAF237) seems to have a protective effect against insulin-induced hypoglycemia.

Table 1 shows the number of patients experiencing one or more episodes (panel A), the total number of episodes (panel B) and the number of severe hypoglycemic episodes (panel C) in patients randomized to 50 mg 15 vildagliptin or placebo added to insulin. In the vildagliptin group, 33 patients reported a total of 113 episodes, none of which were serious, that is, requiring assistance from a third party. In the placebo group, 45 patients reported a total of 185 episodes, 6 of which were severe. Both the number of hypoglycemic events and the number of serious events were statistically significant in the vildagliptin group (P <0.001 and P = 0.032 respectively, based on

20 chi-square test of two degrees of Poisson).

Table 1: Number of patients who report any hypoglycemic episode (panel A), total number of hypoglycemic episodes reported (panel B) and number of severe hypoglycemic episodes (panel C) during 24-week treatment with vildagliptin

50 mg twice daily (n = 144) or placebo (n = 152). * P <0.05), *** P <0.001 versus placebo.

Panel

Vildagliptin patients + Insulin No. of Placebo + Insulin No. of patients

TO

33 Four. Five

B

113 185

C

0 6

In addition, insulin dosage can be reduced in patients treated with LAF237.

Claims (11)

one.

Use of a DPP-IV inhibitor or a salt thereof for the manufacture of a medicament for the reduction of hypoglycemic events or severe hypoglycemic events, in patients being treated with insulin, in which the DPP-IV inhibitor is vildagliptin or a Get out of it.

2.

Use according to claim 1, wherein:

i) a patient treated with insulin is selected and shows hypoglycemic events, preferably severe hypoglycemic events, ii) vildagliptin or a salt thereof in combination with insulin should be administered daily to said patient. 3. Use according to any one of the preceding claims, wherein, i) a patient treated with insulin is selected and shows hypoglycemic events, preferably severe hypoglycemic events, ii) vildagliptin or a salt thereof in combination with insulin should be administered daily to said patient, and in which, iii) the daily insulin dose is progressively reduced until the desired glucose level is achieved. 4. Use according to any one of the preceding claims, wherein, i) a patient treated with insulin is selected and shows hypoglycemic events, preferably severe hypoglycemic events, ii) vildagliptin or a salt thereof in combination with insulin should be administered up to a reduced dose of insulin, daily, to said patient. 5. Use according to any one of the preceding claims, wherein; i) a patient treated with insulin is selected and shows hypoglycemic events, preferably severe hypoglycemic events, ii) 25 to 150 mg, preferably 50 mg or 100 mg of vildagliptin should be administered in combination with insulin, daily, to said patient. 6. Use according to any one of the preceding claims, wherein: i) a patient treated with insulin is selected and shows hypoglycemic events, preferably severe hypoglycemic events, ii) 25 to 150 mg, preferably 50 mg or 100 mg of vildagliptin should be administered in combination with insulin, daily, to said patient, and in which iii) the daily dose or dose of insulin is progressively reduced until the desired glucose level is achieved. 7. Use according to any one of the preceding claims, wherein; i) a patient treated with insulin is selected and shows hypoglycemic events, preferably severe hypoglycemic events, ii) 25 to 150 mg, preferably 50 mg or 100 mg of vildagliptin should be administered in combination with a reduced insulin dosage, daily, to said patient.

8.

Use according to any of the preceding claims, in which the treated patient suffers from hyperglycemia, diabetes mellitus, insulin dependent diabetes mellitus (DMID), diabetes mellitus no

insulin dependent (DMNID), insulin resistance type A, impaired glucose metabolism (IGM), impaired fasting glucose (IFG) or glucose intolerance (IGT).

9.

Use according to any of the preceding claims, wherein the hypoglycemic event is a severe hypoglycemic event.

Use according to any of the preceding claims, in which the patient is a patient whose disease or whose glucose level is not adequately controlled by insulin alone. 11. Use according to any one of the preceding claims, wherein between 25 and 200 mg of vildagliptin or a salt thereof should be administered daily. 12. Use according to any of the preceding claims, wherein it should be administered daily between 10 and 150 mg, preferably 50 mg or 100 mg of vildagliptin, or a salt thereof.